My lab studies gene regulation during development and cancer, and we focus on the regulation and functional consequences of alternative cleavage and polyadenylation (ApA) using genome-wide approaches.
DNA is transcribed into the primary transcript. This transcript needs to be processed into a mature messenger RNA (mRNA), because only mature mRNAs can be translated into protein. mRNA processing consists of capping, splicing, and cleavage at the 3' end with subsequent addition of a poly(A) tail. The recognition of ApA sites leads to the generation of mRNA isoforms that differ in the length of their 3' untranslated regions (3'UTRs). The alternative mRNAs produce the wild-type protein but differ in the presence of regulatory elements located in the 3'UTR, such as localization signals, AU-rich elements, or microRNA binding sites. We showed for specific genes that the shorter mRNA isoforms produce on average tenfold more protein. This suggests that ApA is a gene regulatory mechanism to control protein expression levels.
Half of all human genes generate mRNA isoforms with more than one 3'UTR isoform (multi-UTR genes). We developed a next-generation sequencing method, called 3'-seq, to quantify 3'UTR isoform expression. In close collaboration with Christina Leslie’s lab, we established a computational method that allows us to identify differentially expressed 3'UTR isoforms between samples. We investigated samples from diverse human tissues and found that alternative 3'UTR isoform expression is highly tissue specific. About two-thirds of all multi-UTR genes show a significantly different 3'UTR isoform expression pattern in a least two samples. We call these genes polyadeno-regulated multi-UTR (pAM) genes. During differentiation or transformation only a fraction of the multi-UTR genes change their relative isoform expression. But the genes that change their isoform ratios are highly specific to each perturbation. These genes are involved in tissue-specific processes despite being transcribed ubiquitously.
3’-seq generates a quantitative transcriptome-wide atlas of pA cleavage events.
Lianoglou S, Garg V, Yang JL, Leslie CS, Mayr C. Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression. Genes Dev, 2013. Published in Advance October 21, 2013, doi:10.1101/gad.229328.113
Mayr C, Bartel DP. Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell. 2009 Aug 21;138(4):673-84. doi: 10.1016/j.cell.2009.06.016.
Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008 Nov 27;456(7221):470-6. doi: 10.1038/nature07509.
Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation Science. 2007 Mar 16;315(5818):1576-9. Epub 2007 Feb 22.
Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R, Hallek M, Wendtner CM. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006 Jan 15;107(2):742-51. Epub 2005 Sep 22.
Damon Runyon-Rachleff Innovation Award, Damon Runyon Cancer Research Foundation (2012)
Kimmel Scholar Award, Sidney Kimmel Foundation (2011)
Christine Mayr, who once dreamed of exploring space as an astronaut, today probes new realms in the field of cancer genetics.